The present invention relates to methods for the production of particulate vehicles for the intravenous administration of pharmacologically active agents, novel compositions produced thereby, and methods for in vivo delivery thereof.
The anticancer agent paclitaxel (TAXOL for Injection Concentrate, Bristol Myers Squibb (BMS)) has remarkable clinical activity in a number of human cancers including cancers of the ovary, breast, lung, esophagus, head and neck region, bladder and lymphomas. It is currently approved for the treatment of ovarian carcinoma and non-small cell lung cancer where it is used in combination with cisplatin; for metastatic breast cancer that has failed prior treatment with one combination chemotherapy regimen; and for AIDS-related Kaposi""s sarcoma. The major limitation to the use of paclitaxel is its poor solubility and consequently the BMS formulation (TAXOL) contains Cremophor(copyright) EL as the solubilizing vehicle. Each vial of TAXOL contains 30 mg of paclitaxel dissolved in Cremophor/ethanol vehicle at a concentration of 6 mg/mL. Prior to intravenous administration, this formulation must be diluted 1:10 in saline to produce a final dosing solution containing 0.6 mg/mL of paclitaxel. The presence of Cremophor in this formulation has been linked to severe hypersensitivity reactions in animals (Lorenz et al., 1987, xe2x80x9cHistamine Release in Dogs by Cremphor EL(copyright) and its derivatives: Oxethylated oleic acid is the most effective constituentxe2x80x9d. Agents Actions 7:63-67, 1987) and humans (Weiss et al., 1990, xe2x80x9cHypersensitivity reactions from Taxolxe2x80x9d, J Clin Oncol 8:1263-1268, 1990) and consequently requires premedication of patients with corticosteroids (dexamethasone) and antihistamines. The large dilution results in large volumes of infusion (typical dose 175 mg/m2) in up to one liter and infusion times ranging from three hours to 24 hours. Thus, there is a need for an alternative, less toxic formulation for paclitaxel.
In a study by Holmes (Holmes F A, Walters R S, Theriault R L, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991) and at MKSCC (Reichman B S, Seidman A D, Crown J P A, et al: Paclitaxel and recombinant human granulocyte colony stimulating factor as initial chemotherapy for metastatic breast cancer. Clin Oncol 11:1943-1951, 1993) it was shown that higher doses of TAXOL to 250 mg/m2 produced greater responses (60%) than the 175 mg/m2 dose (26%) currently approved for TAXOL. These results however, have not been reproduced due to higher toxicities at these higher doses. These studies, however, bear proof to the potential increase in response rate at increased doses of paclitaxel. The invention formulations described herein may allow the administration of highter doses then are possible with TAXOL due to lower toxicity of the formulation, thereby exploiting the full potential of this drug.
Bristol-Myers Squibb tested TAXOL in clinical trials on patients previously treated for ovarian and breast cancer that did not respond to standard therapies. Following are summaries of information as reported in the package insert for TAXOL:
Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
With the 24-hour infusion of TAXOL, it appeared that an increase in dose from 135 mg/m2 to 175 mg/m2 (30%) increased the Cmax by 87% whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, the dose increase from 135 to 175 mg/m2 caused an increase in the Cmax and AUC (0-∞) of 68% and 89%, respectively. The mean apparent volume of distribution with the 24-hour infusion of TAXOL ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
In Phase I and II studies, pharmacokinetics of TAXOL were also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54). Values from these studies were consistent with the findings in the above study.
In vitro studies were used to study the binding of paclitaxel to human serum proteins. Between 89-98% of drug was bound for paclitaxel concentrations ranging from 0.1 to 50 xcexcg/mL. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. Mean (SD) values for cumulative urinary recovery of unchanged drug ranged from 1.3% (0.5%) to 12.6% (16.2%) of the dose after intravenous administration, indicating extensive non-renal clearance for 15-275 mg/m2 doses of TAXOL as 1, 6, or 24-hour infusion. Since TAXOL has been demonstrated to be metabolized in the liver in animals, the evidence suggests hepatic metabolism in humans. In addition, high paclitaxel concentrations have been reported in the bile of patients treated with TAXOL. However, effects of renal or hepatic dysfunction on the disposition of paclitaxel have not been investigated.
Review of recent literature indicates that there are several Phase I and II studies in progress to study possible interactions of paclitaxel with concomitantly administered medications. In general, platinum-based concomitant therapies and sequence/time intervals influence both toxicity and efficacy. Also, paclitaxel can function as a radiosensitizer when used in combination with radiation therapy.
The initial approval of the TAXOL formulation of paclitaxel was based on Phase I and II studies of 189 patients and a Phase III study with 407 patients who had failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. In the first 2 studies, response rates were 22% (95% Cl=11-37%) and 30% (95% Cl=18-46%) with a total of six complete and 18 partial responses in 92 patients.
The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2-36.7 months) and 15.9 months (range: 1.8-34.5 months).
The Phase III study compared the efficacy and safety of TAXOL, administered at 135 or 175 mg/m2 paclitaxel with either three or 24 hour infusion schedules. The results are summarized in Table 1.
The most frequently observed adverse events involved myelosuppression with 352 episodes of neutropenia of  less than 2,000/mm3 and 183 episodes of neutropenia of  less than 500/mm3. Episodes of thrombocytopenia with  less than 100,000/m3 and  less than 50,000/m3 were 36 and 11, respectively. Episodes of anemia with  less than 11 g/dL and  less than 8 g/dL were 330 and 39, respectively. There were also 93 episodes of infection. There were 169 episodes of hypersensitivity reactions, five of which were severe. Also there were 220 observations of peripheral neuropathy (with three severe cases) and 98 observations of mucositis (with three severe cases).
The initial approval of the TAXOL formulation of paclitaxel for use on patients with breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy was based on data from 83 patients in three Phase II studies. TAXOL was administered to 53 patients as a 24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2 in two Phase II studies. The response rates were 57% (95% CI: 37-75%) and 52% (95% CI: 32-72%), respectively. A third Phase II study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of two chemotherapy regimens for the treatment of metastatic disease. The dose of TAXOL was 200 mg/m2 paclitaxel as a 24-hour infusion with G-CSF support. Nine of the 30 patients analyzed achieved a partial response, for a response rate of 30% (95% CI: 15-50%).
A multicenter, Phase III trial with 471 patients was conducted in patients previously treated with one or two regimens of chemotherapy. Patients received TAXOL at a dose of either 175 mg/m2 or 135 mg/m2 paclitaxel given as a 3-hour infusion. Sixty percent of the patients had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. All patients had failed prior chemotherapy, 67% had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents. The overall response rate for the 454 evaluable patients was 26% with 17 complete and 99 partial responses. The median duration of response was 8.1 months (range: 3.4-18.1 months) and median survival was 11.7 months (range: 0-18.9 months). Adverse events observed were similar to the type and frequency recorded for ovarian cancer patients treated with paclitaxel. Table 2 shows the incidence of some key adverse events for the Phase III study.
Myelosuppression and peripheral neuropathy were dose-related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.
For the treatment of Non-Small Cell Lung Carcinoma (NSCLC) with TAXOL, 559 patients were randomized to receive either a) TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with Cisplatin 75 mg/m2, b) TAXOL (T) 250 mg/m2 as a 24 hour infusion in combination with Cisplatin 75 mg/m2 with G-CSF support, or c) Cisplatin 75 mg/m2 on day 1, followed by Etoposide 100 mg/m2 on days 1, 2 and 3 (control).
The adverse event profile was consistent with the profile seen in other clinical studies of TAXOL. Response rates were 25% (TAXOL 135 mg/m2, 24 hour infusion, Cisplatin 75 mg/m2); 23% (TAXOL 25 mg/m2, 24 hour infusion, Cisplatin 75 mg/m2), and 12% (Etoposide 100 mg/m2 and Cisplatin 100 mg/m2).
The approval of the TAXOL formulation of paclitaxel for use as a second line defense on patients with AIDS-related Kaposi""s Sarcoma was based on 2 Phase II clinical studies. Paclitaxel doses of 45 mg/m2/week and 50 mg/m2/week were tested. The median time to response was 8.1 weeks and duration of response was 11.0 weeks. Of the 59 patients treated, 3% (2) had complete responses, 56% (33) partial responses, 29% (17) had stable disease, 8% (5) had disease progression and 3% (2) had early death/toxicity. The adverse reactions were similar to patients after treatment for solid tumors. However, patients with AIDS-related Kaposi""s Sarcoma may experience more severe hematologic toxicities.
Thus, there remains a need in the art for alternative methods of delivering pharmacologically active agents, such as paclitaxel.
In accordance with the present invention, we have discovered that substantially water insoluble pharmacologically active agents can be delivered in the form of microparticles or nanoparticles that are suitable for parenteral administration in aqueous suspension. This mode of delivery obviates the necessity for administration of substantially water insoluble pharmacologically active agents (e.g., paclitaxel) in an emulsion containing, for example, ethanol and polyethoxylated castor oil, diluted in normal saline (see, for example, Norton et al., in Abstracts of the 2nd National Cancer Institute Workshop on Taxol and Taxus, Sep. 23-24, 1992). A disadvantage of such known compositions is their propensity to produce allergic side effects.
Thus, in accordance with the present invention, there are provided methods for the formation of nanoparticles of pharmacologically active agents by a solvent evaporation technique from an oil-in-water emulsion prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like), optionally without the use of any conventional surfactants and/or without the use of any polymeric core material to form the matrix of the nanoparticle. Instead, proteins (e.g., human serum albumin) are employed as a stabilizing agent.
The invention further provides methods for the reproducible formation of unusually small nanoparticles (less than 200 nm diameter), which can be sterile-filtered through a 0.22 micron filter. This is achieved by addition of a water soluble solvent (e.g., ethanol) to the organic phase and by carefully selecting the type of organic phase, the phase fraction and the drug concentration in the organic phase. The ability to form nanoparticles of a size that is filterable by 0.22 micron filters is of great importance and significance, since formulations which contain a significant amount of any protein (e.g., albumin), cannot be sterilized by conventional methods such as autoclaving, due to the heat coagulation of the protein.
In accordance with another embodiment of the present invention, we have developed compositions useful for in vivo delivery of substantially water insoluble pharmacologically active agents. Invention compositions comprise substantially water insoluble pharmacologically active agents (as a solid or liquid) coated by an optionally crosslinkable biocompatible polymer, and optionally contained within a polymeric shell. The polymeric shell is a crosslinked biocompatible polymer. The polymeric shell, containing substantially water insoluble pharmacologically active agents therein, can then be suspended in a biocompatible aqueous liquid for administration.
The invention further provides a drug delivery system in which part of the molecules of pharmacologically active agent are bound to the protein (e.g., human serum albumin), and are therefore immediately bioavailable upon administration to a mammal. The other portion of the pharmacologically active agent is contained within nanoparticles coated by protein. The nanoparticles containing the pharmacologically active agent are present as a substantially pure active component, without dilution by much, if any, polymeric matrix.
In accordance with the present invention, there are also provided submicron particles in powder form, which can easily be reconstituted in water or saline. The powder is obtained after removal of water by lyophilization. Human serum albumin serves as the structural component of invention nanoparticles, and also as a cryoprotectant and reconstitution aid. The preparation of particles filterable through a 0.22 micron filter according to the invention method as described herein, followed by drying or lyophilization, produces a sterile solid formulation useful for intravenous injection.
The invention provides, in a particular aspect, a composition of anti-cancer drugs, e.g., paclitaxel, in the form of nanoparticles in a liquid dispersion or as a solid which can be easily reconstituted for administration. Due to specific properties of certain drugs, e.g., paclitaxel, such compositions cannot be obtained by conventional solvent evaporation methods that rely on the use of surfactants. In the presence of various surfactants, very large drug crystals (e.g., size of about 5 microns to several hundred microns) are formed within a few minutes of storage, after the preparation process. The size of such crystals is typically much greater than the allowed size for intravenous injection.
While it is recognized that particles produced according to the invention can be either crystalline, amorphous, or a mixture thereof, it is generally preferred that the drug be present in the formulation in an amorphous form. This would lead to greater ease of dissolution and absorption, resulting in better bioavailability.
In accordance with another embodiment of the present invention, there are provided various methods of administering a pharmacologically active agent which must be administered in multiple doses over a cycle time which is less than the cycle time of administration of non-invention formulations of the pharmacologically active agent.
The invention further provides various methods of reducing the myelosuppressive effects and/or the neurotoxic effects of a pharmacologically active agent administered to a patient in need thereof.
In accordance with yet another embodiment of the present invention, there are provided methods of administering pharmacologically active agent(s) to a patient having a disease capable of treatment by the pharmacologically active agent(s). Invention methods comprise administering formulations according to the invention containing suitable pharmacologically active agent(s) to the patient. Diseases contemplated for treatment according to the invention include cancers, proliferative diseases, and the like. Administration of invention formulations can be accomplished in a variety of ways, e.g., intravenous or intraarterial, and/or can be without the use of steroids and/or cytokines, and/or can be in combination with a biochemotherapy agent; and/or the single dose levels of pharmacologically active agents can be greater than about 50 mg; and/or the cumulative dose levels of pharmacologically active agents can be greater than about 250 mg/m2 every 3 weeks.
In accordance with a further embodiment of the present invention, there are provided methods of delivering a pharmacologically active agent to a localized area of a patient for sustained release of the pharmacologically active agent over an extended period of time (e.g., from about 1 day to about 1 year). Invention methods comprise administering to the patient a suitable pharmacologically active agent in the invention formulation, wherein the invention formulation has been dispersed within a matrix of suitable biocompatible material.
In accordance with yet another embodiment of the present invention, there are provided methods of orally administering pharmacologically active agent(s) to a patient in need thereof. Invention methods comprise orally administering an invention formulation of the pharmacologically active agent(s) in combination with intestinal cell efflux inhibitor(s).
In accordance with still another embodiment of the present invention, there are provided methods of administering a combination of suitable pharmacologically active agent(s) to a patient in need thereof. Invention methods comprise administering to the patient 25-75% of the conventionally effective dosage level of each of the suitable pharmacologically active agent(s) in the invention formulation.
In accordance with the present invention, there are provided methods for the preparation of substantially water insoluble pharmacologically active agents for in vivo delivery. Also provided in accordance with the invention are compositions prepared by the invention method.
ABI-007 is a proprietary new, Cremophor-free, protein stabilized, nanoparticle formulation of the anticancer drug paclitaxel. Based on animal studies and a Phase I open-label, dose-ranging study, it is believed that a Cremophor-free formulation will be significantly less toxic and will not require premedication of patients. Premedication is necessary with TAXOL to reduce the hypersensitivity and anaphylaxis that occurs as a result of Cremophor in the currently approved and marketed Bristol Myers Squibb formulation of paclitaxel.
In contrast to TAXOL, invention formulations of paclitaxel are stabilized with Human Albumin, USP as vehicle. This combination creates a colloid when reconstituted with saline, which is administered by intravenous infusion. By excluding toxic emulsifiers from invention formulations, it may be possible to administer higher doses of paclitaxel at more frequent intervals than is currently possible with TAXOL.
This unique protein formulation of paclitaxel reduces the toxicities associated with TAXOL (and the Cremophor solvent) while maintaining or improving the chemotherapeutic effect of the drug. The potential exists that enhanced efficacy could be seen in solid tumors as a consequence of (i) higher tolerable doses (300 mg/m2), (ii) longer half-life, (iii) prolonged local tumor availability and/or (iv) sustained in vivo release.
It is known that colloidal nanoparticles or particles  less than 200 nm in size tend to concentrate at the tumor site due to leaky vasculatures. This effect has been described for several lipsomal formulations (Papahadjopoulos, et al., 1991; xe2x80x9cSterically Stabilized Liposomes: improvements in pharmacokinetics, and anti-tumor therapeutic efficacyxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. 88,11460,1991; Gabizon, A., 1992, xe2x80x9cSelective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomesxe2x80x9d, Cancer Res., 52,891,1992; Dvorak, et al., 1988, xe2x80x9cIdentification and Characterization of the blood vesels of solid tumors that are leaky to circulating macromoleculesxe2x80x9d, Am. J. Pathol., 133,95,1988; Dunn, et al., 1994, Polystyrene-pol(ethylene glycol) PS-PEG 2000 particles as model systems for site specific drug delivery: The effect of PEG surface density on the in vitro cell interactions and in vivo biodistribution. Pharm, Res., 11:1016-1022 (1994); and Gref, et al, 1994); Biodegradable long-circulating polymeric nanospheres. Science 263:1600-1603 (1994)). It is possible that localized nanoparticles of paclitaxel at the tumor site may result in slow release of the drug at the tumor site resulting in greater efficacy when compared to administration of the drug in its solubilized (Cremophor-containing) form.
An exemplary product according to the invention, referred to herein as ABI-007, is a novel Cremophor-free, protein stabilized nanoparticle formulation of paclitaxel. The major components are unmodified paclitaxel and human albumin (HA). HA is freely soluble in water. No premedication is required, as the risk of hypersensitivity is remote. A Phase I clinical study of ABI-007 in patients with solid tumors showed no hypersensitivity reactions following multiple IV administrations of this drug without any premedication.
Since the key ingredient of the trial product is paclitaxel, the mechanism of its action is identical to that of TAXOL and TAXOTERE(trademark), another taxane used for similar conditions, both of which act as tubulin binding agents. Both promote microtubule assembly resulting in unusually stable tubulin complexes, which interfere with mitosis resulting in cell death.
Bristol Myers Squibb received approval of a New Drug Application for TAXOL for Injection Concentrate for the treatment of ovarian cancer in December, 1992 and for breast cancer in April, 1994. More recently, TAXOL was approved for use in AIDS-related Kaposi""s Sarcoma and in non-small cell lung cancer. TAXOL has also demonstrated remarkable clinical activity in a number of human cancers including cancers of the lung, esophagus, head and neck region, bladder and lymphomas.
The mechanism of action of paclitaxel is well-known and is described in the literature. Paclitaxel is a novel anti-microtubule agent that promotes the assembly of microtubules from tubulin dimers, and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular function. In addition, paclitaxel induces abnormal arrays or xe2x80x9cbundlesxe2x80x9d of microtubules throughout the cell cycle and multiple arrays of microtubules during mitosis.
Paclitaxel is insoluble in aqueous solutions. Therefore, a carrier vehicle must be used in order to administer paclitaxel intravenously. TAXOL utilizes a mixture of Cremophor EL(copyright) (polyoxyethylated castor oil) and approximately 50% dehydrated alcohol, USP as the vehicle for paclitaxel. Severe hypersensitivity and neutropenia, as well as other adverse effects, have been associated with the administration of TAXOL to both research animals and human patients.
In contrast to TAXOL, ABI-007 is a Cremophor-free formulation of paclitaxel nanoparticles stabilized with Human Albumin, USP as vehicle. This combination creates a colloid when reconstituted with saline, which is administered by intravenous infusion. By excluding toxic emulsifiers from ABI-007, it appears possible to administer higher doses of paclitaxel at more frequent intervals than currently possible with TAXOL, and without premedication.
Details of many aspects of the taxanes are discussed in the Physician Desk Reference, 1999, page 2609 for Taxotere and page 799 for Taxol and are incorporated by reference herein in their entirety.
While the invention composition and methods are described herein with reference to TAXOL, all pharmacologically active agents are contemplated for use in invention compositions and methods. For example, broad classes of compounds such as apoptosis inducing agents, antimitotic agents, microtubule or tubulin binding agents, taxanes, epothilones, COX-2 inhibitors, protease inhibitors, natural products of marine origin and their derivatives, marine polyketides such as discodermolide, eleutherobin, sarcodictyin A, and the like, in addition to compounds referenced in related patent applications, are contemplated for use in invention methods and compositions.
A nonlimiting list of epothilones, a new class of antitumor agents, useful for the invention compositions and methods have been referenced in an article by Nicolaou et al. (Angew. Chem. Int. Ed. 1998, 37, 2014-2045).
Invention compositions may be administered by intravenous (IV) infusion or intra-arterial administration over a desired period (e.g., bolus injection, 30 min, 1 hr, 2 hr, 3 hr, 6 hr, 24 hr, 48 hr, 72 hr or 96 hour infusions). Preferred period is no greater than about 3 hours.
For the treatment of brain tumors, e.g., glioblastomas, intra-arterial administration is preferred, especially via the carotid artery (distal to or proximal to the ophthalmic artery). Invention particles are capable of traversing the blood-brain barrier by passing through the leaky vessels supplying the tumor.
The administration or dosage cycle may be repeated in increments of 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or may be repeated with a break in the cycle, for example 3 weeks on a weekly schedule with 1 week off.
Dosage range of invention compositions varies with the potency of the drug in question. For example drugs such as paclitaxel may be administered in a dose range of about 30-500 mg/m2, docetaxel in the range of about 15-250 mg/m2 and epothilones in the range of about 1-200 mg/m2. These ranges are intended to be exemplary and not limiting.
A number of preclinical studies and Phase I open-label, dose-ranging clinical studies have been performed to demonstrate the safety, pharmacokinetics and the potential efficacy of ABI-007. The preclinical studies were a combination of in vitro cytotoxicity studies; efficacy studies in mice; acute toxicity studies in mice; acute toxicity studies in rats; studies of myelosuppression in rats; pharmacokinetics studies in rats and an acute toxicity study in dogs.
The in vitro cytotoxicity study in an in vitro tumor model using L1210 murine leukemia cells demonstrated that ABI-007 has equivalent efficacy to TAXOL.
Efficacy was greater for ABI-007 than TAXOL in female athymic Ncr-nu mice implanted with MX-1 mammary tumor fragments. One hundred percent (100%) of ABI-007-treated animals survived after 103 days compared to 20%-40% surviving in groups treated with equivalent doses of TAXOL.
In a series of three pharmacokinetic studies in rats, the pharmacokinetic profile of paclitaxel, formulated as ABI-007, and TAXOL were shown to be similar, but blood/tissue concentration ratios and rates of metabolism varied significantly. ABI-007 is more rapidly distributed out of the blood and is more slowly metabolized. Tissue levels of radio-labeled paclitaxel were higher in several tissues (prostate, spleen, pancreas, and to a lesser extent bone, kidney, lung, and muscle) following administration of ABI-007 when compared to TAXOL. Excretion of paclitaxel following ABI-007 and TAXOL administration was predominantly in the feces.
Toxicity studies have been conducted in mice, rats, and dogs. Single dose acute toxicity studies in mice showed an LD50 dose approximately 59 times greater for ABI-007 than for TAXOL. In a multiple dose toxicity study in mice, the LD50 dose was approximately 10 fold greater for ABI-007 than for TAXOL.
In a 14 day, acute toxicity study in rats, the animals tolerated ABI-007 at doses up to 120 mg/kg, whereas significant morbidity and mortality were reported at doses of 30 mg/kg of TAXOL. Cerebral cortical necrosis was seen in the TAXOL-treated animals. Testicular degeneration was observed in the ABI-007-treated animals.
A single-dose, acute toxicity study was conducted in dogs to determine if the differences observed in the pharmacokinetic profiles of paclitaxel, after doses of ABI-007 and TAXOL resulted in toxicities in a large animal species. The study was conducted using ABI-007, ABI-007 vehicle control, and Human Albumin, USP. TAXOL was not used because of the severe anaphylactic reaction known to be exhibited by dogs due to the Cremophor in the product. With the exception of testicular degeneration in the males (also seen in the rats), the study did not provide useful information. Animals in all groups (active drug and controls) exhibited significant symptoms, which were attributed to an immune reaction to human albumin.
Two further pilot studies were conducted to evaluate the degree of myelosuppression in rats treated with ABI-007 and TAXOL. The results showed that ABI-007 produces considerably less myelosuppression in rats than TAXOL at a dose of 5 mg/kg. The study of the effects of higher doses of ABI-007 (30, 90, 120, 200 mg/kg) showed a dose response relationship in both myelosuppression and decreased body weights with the effect peaking at day 3.
White blood cell counts were back to normal or were elevated by day 14 in surviving animals. Animals in the high dose study showed symptoms of dose-related toxicity.
In a Phase I, intravenous administration, open-label, dose-ranging trial of ABI-007 therapy in patients with advanced solid tumors conducted at M. D. Anderson Cancer Center, more than 80 courses of ABI-007 were administered intravenously over 30 minutes every 3 weeks to 19 patients. The total number of doses of ABI-007 administered was 83. The maximum dose administered was 375 mg/m2, which was administered to six patients (between 25-85 minutes). The maximally tolerated dose was 300 mg/m2, which was also administered to six patients (between 27-60 minutes). The following data for the Phase I study is preliminary, and is representative of all 19 patients; however, data is still outstanding on three patients, who are currently receiving study drug. The 375 mg/m2 dose was associated with dose-limiting toxicities in three out of the six patients. At dose levels of 135 mg/m2 and less than 200 mg/m2, there were no adverse events of myelosuppression or peripheral neuropathy.
ABI-007 was well tolerated at doses up to 300 mg/m2. Most adverse events were Grade 1 or 2 (93%), required no action (83%) and were resolved (78%). No deaths occurred during the study. Five patients had reductions in their study drug dosages, changes in their frequency, interruptions in dosing and/or discontinuation of study drug during the study. All five patients had these changes to their study drug regimen as the result of the development of unacceptable toxicities. Of these five patients, four reported sensory changes, three reported vision-related toxicities, two patients experienced asthenia and two patients experienced thrombocytopenia. All other patients receiving a dose from 135 mg/m2 to 300 mg/m2 showed no such evidence of thrombocytopenia.
There was a total of 13 (68.4%) patients that reported Absolute Neutrophil Count (ANC) less than 2000 cells/mm3. Of the total 13 patients, 2 (15%) were at a dose level of 135 mg/m2, 1 (8%) patient was at dose level 200 mg/m2, 5 (38%) patients were at dose level 300 mg/m2, and 5 (38%) patients with ANC less than 2000 cells/mm3 were at the dose level of 375 mg/2.
Two (10.5%) patients experienced thrombocytopenia, both dosed at 375 mg/m2. The first patient resolved when dosing level was reduced to 198.86 mg/m2. The second patient resolved without any action taken; however, on the patient""s next dosing cycle, study drug was administered at a slightly lower dose of 361.38 mg/m2.
The most common ( greater than 3% of all 377 reported events) adverse events were asthenia (13.1%), nausea (8.8%), fever (6.8%), sensory changes (6.1%; sensory changes included: sensory loss, tingling, paresthesia, and peripheral neuropathy), arthralgia (5.7%), stomatitis (5.1%), myalgia and headache (both at 4.5%), diarrhea, rash, vomiting, and visual disturbances (all at 4.3%; visual disturbances included: vision abnormalities (2.0%), dry eyes (1.4%), and keratitis (0.9%)), and hypertonia (3.4%).
The adverse events reported by the majority of patients (% of total patients) were asthenia (84.21%), nausea (68.42%), sensory changes (63.16%), rash (57.89%), fever, myalgia, and stomatitis (all at 52.63%), headache (42.11%), diarrhea and vomiting (both at 36.84%), arthralgia (31.58%), and hypertonia (26.32%). Phase I Incidence of Adverse Events, categorized by the number (% of Total) of occurrences and number (% of Total) of patients for administration of ABI-007 is summarized in Table 5 (see Example 12).
Sensory changes and visual disturbances were the only toxicities that appeared to be dose-related. Sensory and vision-related toxicities were rated as Grade 2 and Grade 3, judged to be potentially study drug-related and required changes to the study drug-dosing regimen. Half of the cases reported at the time of the preliminary analysis remained unresolved. These were potentially dose-related toxicities in that 16 out of the 23 reported sensory toxicities and 6 out of the 17 vision-related toxicities occurred in patients receiving  greater than 300 mg/m2.
Nineteen out of the 27 (70.4%) reporting Grade 3 toxicities were rated potentially study drug related. Only 4 (21%) out of the 19 remain unresolved: one fatigue and three cases of sensory changes. These four cases occurred in three different patients and action (study drug dose reduction) was required for only one case of sensory toxicity. Five cases of asthenia, which were rated as Grade 3, occurred in five separate patients. These toxicities were judged as potentially study drug-related in four cases, which required study drug dose regimen changes in two cases (both dosed at 375 mg/m2). Grade 3 sensory changes occurred in four separate patients, all judged as potentially study drug-related and required dose reductions in three cases (patient dosed between 300-375 mg/m2).
In addition, six patients developed potentially study drug related ocular problems, which required dose regimen changes in three cases. Ocular complaints included the following: decreased vision associated with burning sensation, foreign body sensation and photophobia. These patients were found to have superficial keratopathy as the underlying cause of their problems. They required aggressive lubrication and placement of collagen punctual plugs. These events were resolved after dose reduction and treatment of symptoms in two cases. This data is not inclusive of all resolutions. Two cases remained unresolved at the time of the preliminary analysis.
Two patients developed unacceptable toxicities, which warranted discontinuation from the study in the opinion of the Principal Investigator. The first patient received cycle one dosing of ABI-007 at 300 mg/m2, and was reduced to 200 mg/m2 due to subsequent development of Grade 1 arthralgia and Grade 3 sensory changes. This patient continued on the study for four additional cycles, with no acute toxicities. The second patient received one dosing cycle at 370.83 mg/m2, with no acute toxicities; however, both patients later developed multiple toxicities and were discontinued from the study.
In conclusion, based on information available to date, ABI-007, a Cremophor-free nanoparticle formulation of paclitaxel, provides a new efficient method of treating patients with paclitaxel with lower toxicity to the patient, allowing treatment with higher therapeutic doses of the active drug substance, without the need for premedication.
Taxanes constitute a new antineoplastic class approved and administered since 1992 for the treatment of ovarian cancer and 1994 breast cancer. More recently, taxanes were approved for the use in Kaposi""s sarcoma, in some human cancers including lung, esophagus, head and neck, bladder and lymphomas. As improved formulations of paclitaxel are developed, it is expected that additional indications will benefit from treatment with paclitaxel, e.g., glyblastomas.
Paclitaxel promotes the assembly of microtubules and stabilizes the microtubules by preventing depolymerization. This stability inhibits the normal dynamic reorganization of the microtubule that is essential for vital interphase and mitotic cellular function.
Paclitaxel is insoluble in aqueous solutions, therefore a carrier vehicle must be used, e.g., a mixture of polyoxyethylated castor oil (Cremophor EL) and dehydrated alcohol. Acute reactions such as hypotension, dispnea, bronchospasm, changes in heart rate, urticaria have been associated with the administration of this vehicle. For this reason it is required to perform a pre-medication with prednisone, cimeditine, clorfenamine and hydrocortisone. Severe leucopenia and neutropenia are less frequent in short administrations than in long infusions.
The new formulation of paclitaxel nanoparticles stabilized with human albumin ( less than 200 nm), creating a colloid when reconstituted with saline, is easier to handle than the prior art paclitaxel-containing formulations, with an unchanged cytotoxicity and with an acute toxicity in the animal 60 times inferior to Taxol.
In research animals myelosuppression is inferior and the anaphylactic reactions are absent. The colloid shows chemical-physical characteristics suitable with the injection performed using very small catheters. Viscosity is low and is compatible with the plastic materials.
After endovenous administration the total tissue concentration of ABI-007 is higher than that observed with Taxol; in vivo, ABI-007 is slowly metabolized so the cytotoxic activity of ABI-007 is longer than the one reported with Taxol.
From preliminary observations it is possible to assess that taxanes are more active in the squamouscellular carcinoma because this type of tumours show a major presence of the growth factor receptor. The hypothesis is that the taxanes could interfere in the process mediated by the receptor.
Taxane activity per systemic treatment in the advanced head and neck carcinoma aren""t numerous. The efficacy of paclitaxel per endovenous treatment as a single agent in the relapse is superior with respect to the standard chemotherapic combinations (cisplatin, 5 FU), however the improvement is not so relevant. Considering the recently developed taxanes, such as docetaxel, the objective responses (complete-partial response) in the relapses go from 30 to 42%.
Less than 30% of patients with advanced local tumours (state III/IV) can be subjected to surgery and/or radiotherapy.
Three cycles of Cisplatin-Fuorouracil treatment show a clinical complete response in the 30-50% of the patients with relevant toxicity. The improvement of patients"" survival hasn""t been observed with this neoadjuvant treatment, as a recovery of the loco-regional tumour or the presence of metastases have occurred. A high T takes to a local relapse and it""s more difficult to obtain a clinical response or a complete pathological response.
The intent to improve the neoadjuvant chemotherapy in the oral and oro-hypopharynx carcinoma, is justified by assessing a final local therapy through surgery or radiotherapy in order to reach a good life-style or to protect the organ.
An intra-arterial chemotherapy with cytostatics was conducted in the past and recently resumed after cisplatin introduction; moreover the technique and the new material for catheterism permitted to improve the procedure reducing the risks. The response registered (clinical-radiological complete and partial) goes from 47 to 94% in patients with advanced disease or relapse.
At Istituto Nazionale per lo Studio e la Cura dei Tumouri did Milano (INT) is going to close a phase I study with ABI-007 intra-arterial administration in solid tumour especially loco-regional type with the enrolment of about 100 patients.
Twenty-three patients with squamous-cellular head and neck carcinoma, stage IV, not treated (10), with relapse after surgery+RT+chemotherapy (5), surgery+radiotherapy (3), radiotherapy+chemotherapy (1), surgery+chemotherapy (2), radiotherapy (1), surgery (1). ABI-007 was administered intra-arterial every 4 weeks for 3 cycles. The maximum dose was of 270 mg/m2.
All 23 patients were evaluable for toxicity : 86.36% alopecia (I, II), 77.27% simile-flu syndrome (I, II), 68.18% midollar (I-II, 1 Pt grade 4), 45.45% neurological (I-II), 50% gastro-intestinal (I-II), 27.27% cutaneous (I-II) and 22.72% ocular (I-II). In 80 cases evaluated, one serious adverse event occurred. One patient with head and neck carcinoma with concomitant cirrhosis died after esophageal varices rupture. In this case, the dose was 300 mg/m2 and caused a grade IV haematological toxicity.
The efficacy was assessed in 20 patients valuable for T: CR (pathological) 2 (10%), PR 12 (60%), MR (15%), SD (15%), PRO 2 (10%).
The complications using catheterization of cerebral vessels evaluated on 23 patients for 60 procedures are 5%. Three patients suffered from hemi paresis (1 case) a temporary cerebral ischaemia; these complications are spontaneously recovered.
The quality of life in patients subjected to intra-arterial therapy was remarkable with a local and systemic toxicity acceptable, especially with ABI-007 (230 mg/m2 dose). This dose will be administered each 4 weeks (xc2x13 days) for the Phase II study.